Wound healing involves a well-coordinated series of biological processes that include both tissue destruction and tissue regeneration. For example, during normal wound healing, neutrophils and monocytes are recruited to the wound during an early inflammatory phase. The neutrophils phagocytize debris and micro-organisms; monocytes and other cells release enzymes in the surrounding matrix to digest damaged tissue. Fibrin is broken down as part of this process, and the degradation products attract fibroblasts and epithelial cells to the site of the wound. Macrophages recruited to the wound (as well as other cells) secrete extracellular enzymes that act on all components of the extracellular matrix and are responsible for removal of devitalized tissue. Macrophages also secrete a variety of cytokines and growth factors that can stimulate keratinocytes, fibroblasts and angiogenesis, which promotes the transition to the proliferative phase of healing. The proliferation phase is characterized by angiogenesis, collagen deposition, granulation tissue formation, wound contraction and epithelialization. Proliferation involves replacement of dermal tissues as well as contraction of the wound.
While destruction of collagen is important during the early phases of wound healing, its deposition and remodeling is critical for later stages. During wound healing, the wound bed fills in from the bottom up with collagen and must be maintained in an optimal environment (appropriate moisture balance and temperature) before the epithelial cells will begin to proliferate and migrate across the wound's surface to close the wound. The collagen structures provide the cells with the needed biological environment for development, organogenesis, cell growth, and wound repair.
Chronic wounds are wounds that have not progressed through this normal, orderly sequence of repair. Further, chronic wounds may eventually pass through the repair process without restoring sustained anatomical and functional tissue. Chronic wounds can result when the body has failed to correct for the causes of the wound, and/or where there is not a conducive environment for healing. For example, newly deposited collagen can be enzymatically destroyed by an uncontrolled inflammatory response, making it difficult for dermal cells to populate the wound and proliferate.
The present invention provides compositions and methods for promoting wound healing, including for acute and chronic wounds, and wounds that result from physical, biological, or genetic causes that interfere with normal wound healing physiology.